Pharmaceutical substances need to be in dissolved state in order to be able to have an influence in human or animal body. Because of this, dissolution properties of solid-state pharmaceutical substances is one of the most important targets of studying in pharmaceutical research and development. In early development phase of new drugs, the number of candidate compounds is very large but the amount of each compound available is very small. Thus, traditional dissolution rate and solubility tests cannot be made. This problem field is discussed e.g. in Lipinski C A, et al: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46: 3-26, 2000.
Other relatively current dissolution testing instruments and challenges of small-volume dissolution testing in pharmaceutical development are presented in Crist G. B., 2009 Trends in Small-Volume Dissolution Apparatus for Low-Dose Compounds, Dissolution Technologies, February 2009 and Scheubel E. et al, Small Volume Dissolution Testing as a Powerful Method during Pharmaceutical Development, Pharmaceutics 2010, 2, 351-363; doi:10.3390/pharmaceutics2040351.
In modern drug development, qualitative methods which guide the development process, are used. Such methods include kinetic solubility tests and computer simulations. These methods can be used to roughly rank different agents based on solubility estimates obtained. However, the qualitative methods suffer from severe drawbacks and it is not uncommon to obtain for example a solubility estimate which deviates from the real solubility by a factor of ten.
There are no methods available which suit for dissolution property testing of large numbers of very small sample amounts, such as individual particles of the substance of interest. Using chemical analysis, it is demanding and resource consuming to get accurate results using small sample amounts. In addition, the chemical analysis methods are specific to the substance used, and therefore non-universal, raising the need for substance consuming and specific method development with continuous validation of new testing methods.
There are also microscopic methods, which utilize manual affixation of the particles by clamping or gluing to a support, and imaging the particles as they dissolve in the affixed position. While microscopic imaging is a non-specific method compared with chemical analysis and suits for all substances, these methods are, however laborious and therefore unsuited for drug development involving a high number of samples. The main problem in these methods is the affixation of the samples so that they both dissolve, i.e. come in contact with the solvent used, and are simultaneously able to be imaged. This would need to be done in very short time frame and with as little human interaction as possible, which has proven to be challenging. In addition, the surface or structure of the particles may be damaged during the affixation process.
An article by Svanbäck, S., et al., Optical microscopy as a comparative analytical technique for single-particle dissolution studies, Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.04.036, widely discusses the option to use optical microscopy for particle dissolution studies. In particular, it is demonstrated that data obtained by optical digital microscopy and UV-spectrophotometry, as a widely-used representative of chemical analysis methods, produce practically identical dissolution curves, with equal variance, for dissolving single particles of model acidic and basic drug compounds. Thus, image analysis can indeed be used, on its own, as a viable analytical technique in single-particle dissolution studies. However, Svanbäck et al. describes a method for characterizing the dissolution rate from an individual particle in a stagnant liquid. The particle in such stagnant system is not trapped, rather immovable or fixed. An essential feature of dissolution property characterization is the capability of changing the flow rate of the dissolution medium, during or between experiments, and the capability of characterizing a particle/s in a stagnant or flowing medium. Thus, the problem relating to maintaining the particle in a fixed position for fast imaging remains.
US 2010/288043 relates to method and apparatus for improving measurements of particle or cell characteristics, such as mass, in Suspended Microchannel Resonators (SMR's), and describes several methods for mechanical trapping of particles or cells. Imaging in the device of this US-application is used as a feedback for the trapping, not for characterization of the particles. In the device changing of flow directions is necessary for the hydrodynamic trapping of particles. This is, however, disadvantageous in dissolution property characterization, as the flow rate and direction directly influences the acquired data.
Thus, there is a need for improved imaging-based dissolution testing methods.